Mechanisms Involved in Epileptogenesis in Alzheimer's Disease and Their Therapeutic Implications

Altres ajuts: Fondo de Investigaciones Sanitario (FIS); National Institutes of Health (1R01AG056850-01A1, R21AG056974, R01AG061566); Fundació La Marató de TV3 (20141210); Sociedad Catalana de Neurología (SCN-2020 to MCI); Fundació Catalana Síndrome de Down; Fundació Víctor Grífols i Luca; Fundación Tatiana Pérez de Guzmán el Bueno.Epilepsy and Alzheimer's disease (AD) incidence increases with age. There are recip-rocal relationships between epilepsy and AD. Epilepsy is a risk factor for AD and, in turn, AD is an independent risk factor for developing epilepsy in old age, and abnormal AD biomarkers in PET and/or CSF are frequently found in late-onset epilepsies of unknown etiology. Accordingly, epilepsy and AD share pathophysiological processes, including neuronal hyperexcitability and an early excitatory-inhibitory dysregulation, leading to dysfunction in the inhibitory GABAergic and excitatory glutamatergic systems. Moreover, both β-amyloid and tau protein aggregates, the anato-mopathological hallmarks of AD, have proepileptic effects. Finally, these aggregates have been found in the resection material of refractory temporal lobe epilepsies, suggesting that epilepsy leads to amyloid and tau aggregates. Some epileptic syndromes, such as medial temporal lobe epilepsy, share structural and functional neuroimaging findings with AD, leading to overlapping symptomatology, such as episodic memory deficits and toxic synergistic effects. In this respect, the existence of epilepti-form activity and electroclinical seizures in AD appears to accelerate the progression of cognitive decline, and the presence of cognitive decline is much more prevalent in epileptic patients than in elderly patients without epilepsy. Notwithstanding their clinical significance, the diagnosis of clinical seizures in AD is a challenge. Most are focal and manifest with an altered level of consciousness without motor symptoms, and are often interpreted as cognitive fluctuations. Finally, despite the frequent association of epilepsy and AD dementia, there is a lack of clinical trials to guide the use of antiseizure medications (ASMs). There is also a potential role for ASMs to be used as disease-modifying drugs in AD

Changing gears to neutral in a polymorph of one-dimensional arrays of cogwheel-like pairs of molecular rotors

We report on a polymorph (2) of an amphidynamic crystal of molecular rods with two helical 1,4-bis(ethynyl)bicyclo[2.2.2]octane rotators where half of the rod-like molecules appear to be shifted with respect to their closest neighbours. This translation takes cogwheel-like pairs of rotators apart in the lattice in such a way that their motion becomes uncorrelated. This property is to be contrasted with the highly correlated motion found to govern the rotators in a recently-published polymorph 1 of the same material. As with polymorph 1, this motion is shown to take place independently of mutations in the handedness of the rotators and of the ‘mutamer’-induced second harmonic generation

Static Modulation Wave of Arrays of Halogen Interactions Transduced to a Hierarchy of Nanoscale Change Stimuli of Crystalline Rotors Dynamics

Here we present a study where what can be seen as a static modulation wave encompassing four successive arrays of interacting iodine atoms in cryst. 1,​4-​Bis((4\u27-​(iodoethynyl)​phenyl) ethynyl)​bicyclo[2,​2,​2]​octane rotors changes the structure from one-​half mol. to three-​and-​a-​half mols. in the asym. unit below a phase transition at 105 K.  The remarkable finding is that the total 1H spin-​lattice relaxation rate, T1-​1, of unprecedented complexity to date in mol. rotors, is the weighted sum of the relaxation rates of the four contributing rotors relaxation rates, each with distinguishable exchange frequencies reflecting Arrhenius parameters with different activation barriers (Ea) and attempt frequencies (τo-​1)​.  This allows us to show in tandem with rotor-​environment interaction energy calcns. how the dynamics of mol. rotors are able to decode structural information from their surroundings with remarkable nanoscale precision

On the possibility of magneto-structural correlations: detailed studies of di-nickel carboxylate complexes

A series of water-bridged dinickel complexes of the general formula [Ni<sub>2</sub>(μ<sub>2</sub>-OH<sub>2</sub>)(μ2- O<sub>2</sub>C<sup>t</sup>Bu)<sub>2</sub>(O<sub>2</sub>C<sup>t</sup>Bu)2(L)(L0)] (L = HO<sub>2</sub>C<sup>t</sup>Bu, L0 = HO<sub>2</sub>C<sup>t</sup>Bu (1), pyridine (2), 3-methylpyridine (4); L = L0 = pyridine (3), 3-methylpyridine (5)) has been synthesized and structurally characterized by X-ray crystallography. The magnetic properties have been probed by magnetometry and EPR spectroscopy, and detailed measurements show that the axial zero-field splitting, D, of the nickel(ii) ions is on the same order as the isotropic exchange interaction, J, between the nickel sites. The isotropic exchange interaction can be related to the angle between the nickel centers and the bridging water molecule, while the magnitude of D can be related to the coordination sphere at the nickel sites

A Crystalline Hybrid of Paddlewheel Copper(II) Dimers and Molecular Rotors: Singlet-triplet Dynamics Revealed by Variable-temperature Proton Spin-lattice Relaxation

10.1002/zaac.20130062

Periodontal disease's contribution to Alzheimer's disease progression in Down syndrome

Altres ajuts: This study was supported by National institutes of Health (NIH)/National Institute on Aging grants AG035137, AG032554, AG12101, AG022374, and AG13616, NIH DE023139-02, Alzheimer's Association NIRG-12-173937, and NIH/NCATS UL1 TR000038. Conflict of interest: No conflict of interest is reported for A.R.K., M.J., P.C., R.G.C., D.S., K.R.C.A., M.R., A.M., J.O.F., S.V., M.C.-I., and B.B. M.J. de Leon has a patent on an image analysis technology that was licensed to Abiant Imaging, Inc., by NYU, and has a financial interest in this license agreement, and NYU holds stock options on the company. M. de Leon has received compensation for consulting services from Abiant Imaging. Dr L. Glodzic was a principal investigator on an Investigator-Initiated project funded by Forest Laboratories and received an honorarium for serving as a consultant to Roche Pharma. Contributors: A.R.K., M.J.de.L., and J.F. wrote the manuscript. All the other authors reviewed the manuscript and contributed with the scientific literature, concepts, and modeling. All authors reviewed the manuscript for intellectual content and approved the final draft.People with Down syndrome (DS) are at an increased risk for Alzheimer's disease (AD). After 60 years of age, >50% of DS subjects acquire dementia. Nevertheless, the age of onset is highly variable possibly because of both genetic and environmental factors. Genetics cannot be modified, but environmental risk factors present a potentially relevant intervention for DS persons at risk for AD. Among them, inflammation, important in AD of DS type, is potential target. Consistent with this hypothesis, chronic peripheral inflammation and infections may contribute to AD pathogenesis in DS. People with DS have an aggressive form of periodontitis characterized by rapid progression, significant bacterial and inflammatory burden, and an onset as early as 6 years of age. This review offers a hypothetical mechanistic link between periodontitis and AD in the DS population. Because periodontitis is a treatable condition, it may be a readily modifiable risk factor for AD

Synaptic phosphorylated a-synuclein in dementia with Lewy bodies

Dementia with Lewy bodies is characterized by the accumulation of Lewy bodies and Lewy neurites in the CNS, both of which are composed mainly of aggregated a-synuclein phosphorylated at Ser129. Although phosphorylated a-synuclein is believed to exert toxic effects at the synapse in dementia with Lewy bodies and other a-synucleinopathies, direct evidence for the precise synaptic localization has been difficult to achieve due to the lack of adequate optical microscopic resolution to study human synapses. In the present study we applied array tomography, a microscopy technique that combines ultrathin sectioning of tissue with immunofluorescence allowing precise identification of small structures, to quantitatively investigate the synaptic phosphorylated a-synuclein pathology in dementia with Lewy bodies. We performed array tomography on human brain samples from five patients with dementia with Lewy bodies, five patients with Alzheimer’s disease and five healthy control subjects to analyse the presence of phosphorylated a-synuclein immunoreactivity at the synapse and their relationship with synapse size. Main analyses were performed in blocks from cingulate cortex and confirmed in blocks from the striatum of cases with dementia with Lewy bodies. A total of 1 318 700 single pre- or post-synaptic terminals were analysed. We found that phosphorylated a-synuclein is present exclusively in dementia with Lewy bodies cases, where it can be identified in the form of Lewy bodies, Lewy neurites and small aggregates (50.16 mm3). Between 19% and 25% of phosphorylated a-synuclein deposits were found in presynaptic terminals mainly in the form of small aggregates. Synaptic terminals that co-localized with small aggregates of phosphorylated a-synuclein were significantly larger than those that did not. Finally, a gradient of phosphorylated a-synuclein aggregation in synapses (pre4pre + post4post-synaptic) was observed. These results indicate that phosphorylated a-synuclein is found at the presynaptic terminals of dementia with Lewy bodies cases mainly in the form of small phosphorylated a-synuclein aggregates that are associated with changes in synaptic morphology. Overall, our data support the notion that pathological phosphorylated a-synuclein may disrupt the structure and function of the synapse in dementia with Lewy bodies.Peer ReviewedPostprint (author's final draft

Impact of the multiscale viscoelasticity of quasi-2D self-assembled protein networks on stem cell expansion at liquid interfaces

Although not typically thought to sustain cell adhesion and expansion, liquid substrates have recently been shown to support such phenotypes, providing protein nanosheets could be assembled at corresponding liquid-liquid interfaces. However, the precise mechanical properties required from such quasi-2D nanoassemblies and how these correlate with molecular structure and nanoscale architecture has remained unclear. In this report, we screen a broad range of surfactants, proteins, oils and cell types and correlate interfacial mechanical properties with stem cell expansion. Correlations suggest an impact of interfacial viscoelasticity on the regulation of such behaviour. We combine interfacial rheology and magnetic tweezer-based interfacial microrheology to characterise the viscoelastic profile of protein nanosheets assembled at liquid-liquid interfaces. Based on neutron reflectometry and transmission electron microscopy data, we propose that the amorphous nanoarchitecture of quasi-2D protein nanosheets controls their multi-scale viscoelasticity which, in turn, correlates with cell expansion. This understanding paves the way for the rational design of protein nanosheets for microdroplet and bioemulsion-based stem cell manufacturing and screening platforms

Diagnostic Accuracy of Magnetic Resonance Imaging Measures of Brain Atrophy Across the Spectrum of Progressive Supranuclear Palsy and Corticobasal Degeneration

The accurate diagnosis of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) is hampered by imperfect clinical-pathological correlations.To assess and compare the diagnostic value of the magnetic resonance parkinsonism index (MRPI) and other magnetic resonance imaging-based measures of cerebral atrophy to differentiate between PSP, CBD, and other neurodegenerative diseases.This prospective diagnostic study included participants with 4-repeat tauopathies (4RT), PSP, CBD, other neurodegenerative diseases and available MRI who appeared in the University of California, San Francisco, Memory and Aging Center database. Data were collected from October 27, 1994, to September 29, 2019. Data were analyzed from March 1 to September 14, 2021.The main outcome of this study was the neuropathological diagnosis of PSP or CBD. The clinical diagnosis at the time of the MRI acquisition was noted. The imaging measures included the MRPI, cortical thickness, subcortical volumes, including the midbrain, pons, and superior cerebellar peduncle volumes. Multinomial logistic regression models (MLRM) combining different cortical and subcortical regions were defined to discriminate between PSP, CBD, and other pathologies. The areas under the receiver operating characteristic curves (AUROC) and cutoffs were calculated to differentiate between PSP, CBD, and other diseases.Of the 326 included participants, 176 (54%) were male, and the mean (SD) age at MRI was 64.1 (8.0) years. The MRPI showed good diagnostic accuracy for the differentiation between PSP and all other pathologies (accuracy, 87%; AUROC, 0.90; 95% CI, 0.86-0.95) and between 4RT and other pathologies (accuracy, 80%; AUROC, 0.82; 95% CI, 0.76-0.87), but did not allow the discrimination of participants with CBD. Its diagnostic accuracy was lower in the subgroup of patients without the canonical PSP-Richardson syndrome (PSP-RS) or probable corticobasal syndrome (CBS) at MRI. MLRM combining cortical and subcortical measurements showed the highest accuracy for the differentiation between PSP and other pathologies (accuracy, 95%; AUROC, 0.98; 95% CI, 0.97-0.99), CBD and other pathologies (accuracy, 83%; AUROC, 0.86; 95% CI, 0.81-0.91), 4RT and other pathologies (accuracy, 89%; AUROC, 0.94; 95% CI, 0.92-0.97), and PSP and CBD (accuracy, 91%; AUROC, 0.95; 95% CI, 0.91-0.99), even in participants without PSP-RS or CBS at MRI.In this study, the combination of widely available cortical and subcortical measures of atrophy on MRI discriminated between PSP, CBD, and other pathologies and could be used to support the diagnosis of 4RT in clinical practice

The Behavioral and Psychological Symptoms of Dementia in Down Syndrome (BPSD-DS) Scale:Comprehensive Assessment of Psychopathology in Down Syndrome

People with Down syndrome (DS) are prone to develop Alzheimer's disease (AD). Behavioral and psychological symptoms of dementia (BPSD) are core features, but have not been comprehensively evaluated in DS. In a European multidisciplinary study, the novel Behavioral and Psychological Symptoms of Dementia in Down Syndrome (BPSD-DS) scale was developed to identify frequency and severity of behavioral changes taking account of life-long characteristic behavior. 83 behavioral items in 12 clinically defined sections were evaluated. The central aim was to identify items that change in relation to the dementia status, and thus may differentiate between diagnostic groups. Structured interviews were conducted with informants of persons with DS without dementia (DS, n = 149), with questionable dementia (DS+Q, n = 65), and with diagnosed dementia (DS+AD, n = 67). First exploratory data suggest promising interrater, test-retest, and internal consistency reliability measures. Concerning item relevance, group comparisons revealed pronounced increases in frequency and severity in items of anxiety, sleep disturbances, agitation & stereotypical behavior, aggression, apathy, depressive symptoms, and eating/drinking behavior. The proportion of individuals presenting an increase was highest in DS+AD, intermediate in DS+Q, and lowest in DS. Interestingly, among DS+Q individuals, a substantial proportion already presented increased anxiety, sleep disturbances, apathy, and depressive symptoms, suggesting that these changes occur early in the course of AD. Future efforts should optimize the scale based on current results and clinical experiences, and further study applicability, reliability, and validity. Future application of the scale in daily care may aid caregivers to understand changes, and contribute to timely interventions and adaptation of caregiving